Myocardial oxygen delivery is intimately dependent on regulation of tone in coronary resistance vessels via extrinsic neurohumoral mechanisms and intrinsic local vasomotor control mechanisms. Local control is imparted primarily by metabolic responses, pressure-induced myogenic responses, and flow-dependent mechanisms in the control of vascular resistance at different levels of the coronary microcirculation is not well known. In addition, the interaction between these mechanisms for integrative control of coronary vasomotor tone has not been established. The overall goal of this proposal is to specifically determine the predominant regulatory mechanisms in different branching orders of coronary arterioles. The role of the endothelium in the functional modulation of these local regulatory mechanisms will also be assessed. These experiments will be performed in four different branching orders of porcine coronary arterioles and small arteries (less than 40, 50-90, 100-150, and 160-250 microsm diameter) using isolated, cannulated vessel techniques to allow pressure, flow, and concentration of metabolic vasodilators to be controlled. We will test four specific hypotheses in this proposal: 1) Myogenic responsiveness varies inversely with arteriolar diameter. 2) The relative magnitude of flow-dependent dilation increases in proportion to diameter, and this response is modulated by the endothelium. 3) Myogenic and flow-dependent responses interact additively or competitively to determine vasomotor tone. Specifically, the interaction will be most prominent in intermediate-size vessels, which I postulate both types of local regulatory mechanisms. 4) The metabolic vasodilatory response becomes more prominent with decreasing arteriolar size, and this response modulates pressure and flow induced responses of coronary microvessels. The results of these studies will provide new and unique information about local regulatory mechanisms at different levels in the coronary microcirculation. This information is essential toward a more complete understanding of regulation of coronary blood flow during coronary heart disease.